Chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated. METHOD: We analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al. RESULTS: Overall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS. CONCLUSION: The methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.

Predictive role of Apparent Diffusion Coefficient (ADC) from Diffusion Weighted MRI in patients with sacral chordoma treated with carbon ion radiotherapy (CIRT) alone.

PURPOSE: To evaluate if baseline ADC from DWI sequences could predict response to treatment in patients with sacral chordoma not suitable for surgery treated with carbon ion radiotherapy (CIRT) alone compared with volume changes. METHODS: Fifty-nine patients with sacral chordoma not suitable for surgery underwent one cycle of CIRT alone and a minimum of 12-months follow-up. All patients underwent MRI before treatment (baseline), every three months in the first two years after treatment, and every six months afterwards. For each MRI, lesion volume was obtained and median, kurtosis, and skewness ADC were analyzed within the whole lesion volume. Volume changes between baseline and the last available follow-up were used to divide patients with partial response, progression of disease and stable disease (PR, PD, and SD). RESULTS: Ten patients were excluded since DWI sequences from baseline MRI were not available. ADC maps obtained from baseline DWI examinations of 50 lesions in the remaining 49 patients were considered. Seven lesions were categorized as PD, 30 PR, and 13 SD. PD showed significantly higher median ADC values at baseline (p = 0.003) compared with both PR and SD (1665vs1253vs1263 *10-6 mm²/s), and more negative skewness values (-0.26vs0.26vs0.08), although not significantly different (p = 0.16). CONCLUSIONS: Preliminary results suggest that baseline ADC could predict response to treatment with CIRT, particularly to detect potential non-responder patients.

Proton and carbon ion radiotherapy in skull base chordomas: a prospective study based on a dual particle and a patient-customized treatment strategy.

BACKGROUND: The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT). METHODS: We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes. RESULTS: After a median follow-up of 44 (range, 6-87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients. CONCLUSIONS: Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC. KEY POINTS: • Proton and carbon ion therapy are effective and safe in skull base chordoma.• Prognostic factors are GTV, organs at risk compression, and dose coverage.• Dual particle therapy and customized strategy was adopted.

Brain MR findings in patients treated with particle therapy for skull base tumors.

Nowadays, hadrontherapy is increasingly used for the treatment of various tumors, in particular of those resistant to conventional radiotherapy. Proton and carbon ions are characterized by physical and biological features that allow a high radiation dose to tumors, minimizing irradiation to adjacent normal tissues. For this reason, radioresistant tumors and tumors located near highly radiosensitive critical organs, such as skull base tumors, represent the best target for this kind of therapy. However, also hadrontherapy can be associated with radiation adverse effects, generally referred as acute, early-delayed and late-delayed. Among late-delayed effects, the most severe form of injury is radiation necrosis. There are various underlying mechanisms involved in the development of radiation necrosis, as well as different clinical presentations requiring specific treatments. In most cases, radiation necrosis presents as a single focal lesion, but it can be multifocal and involve a single or multiple lobes simulating brain metastasis, or it can also involve both cerebral hemispheres. In every case, radiation necrosis results always related to the extension of radiation delivery field. Multiple MRI techniques, including diffusion, perfusion imaging, and spectroscopy, are important tools for the radiologist to formulate the correct diagnosis. The aim of this paper is to illustrate the possible different radiologic patterns of radiation necrosis that can be observed in different MRI techniques in patients treated with hadrontherapy for tumors involving the skull base. The images of exemplary cases of radiation necrosis are also presented.

Feasibility of Carbon Ion Radiotherapy in the Treatment of Gynecological Melanoma.

BACKGROUND: Malignant melanoma of the lower genital tract is a rare disease known to have a poor prognosis. Because of the high rate of distant metastasis and unsatisfactory survival benefit, a more conservative treatment approach, instead of extensive surgery, may be warranted. Gynecological melanoma is a radioresistant tumor, an ideal disease to test the biological efficacy of carbon ion radiotherapy (CIRT). AIM: To report our preliminary experience with CIRT in the treatment of gynecological melanoma at the National Center of Oncological Hadrontherapy (CNAO). PATIENTS AND METHODS: Between January 2016 and February 2017, four patients were admitted for CIRT at CNAO. A case of cervical melanoma was treated with palliative aim because of large volume macroscopic disease, while three cases of vaginal melanoma were irradiated with a total dose of 68.8 Gy (relative biological effectiveness) in 16 fractions delivered over 4 weeks (4 days a week). RESULTS: The age of women ranged between 49 and 72 (median=60.5 years) years. Treatment was well tolerated in all patients and all women completed the scheduled treatment course. During CIRT, toxicity was mild. For patients with vaginal disease, local control was 10.23 and 12.6 months, while that for cervical malignant melanoma was 7.3 months. All patients experienced systemic progression, with median distant metastasis-free survival of 11.7 months. The median overall survival for the whole patient group was 11.41 months. CONCLUSION: In our first experiences, CIRT appears to be a safe non-invasive option for malignant melanoma of the lower genital tract, but more data and longer follow-up are necessary in order to evaluate the effectiveness and late effects.

Carbon Ion Radiotherapy in the Management of Unusual Liposarcomas: A Case Report.

BACKGROUND: Liposarcomas are the most common soft-tissue sarcomas in adulthood. Orbital and spermatic cord liposarcomas are uncommon and there is no consensus on their management. The treatment of choice is wide excision, which may be destructive and lead to unacceptable morbidity. When surgery is declined by patients and in recurrent disease, management can be challenging. We report two cases of liposarcoma treated with carbon ion radiotherapy at the National Center for Oncological Hadrontherapy (Fondazione CNAO) in Italy. CASE REPORT: A woman with orbital liposarcoma and a man with spermatic cord liposarcoma were referred to our Center and accepted for carbon ion radiotherapy. The treatment was well tolerated and late toxicities were mild. Good local control was achieved in patients. CONCLUSION: In our experience, carbon ion radiotherapy is an effective and safe option, especially in cases of tumor at high risk for local relapse, in patients with multiple local recurrences, and in patients who refuse destructive surgery.

Carbon Ion Radiotherapy in the Management of the Tumors of the Peripheral Nervous System.

BACKGROUND/AIM: Malignant peripheral nerve sheaths tumors (MPNST) are rare, highly aggressive and radioresistant tumors of soft tissue. Carbon ion radiotherapy (CIRT) seems to be an attractive treatment option when surgery is not possible or refused by the patient. The aim of this study was to report our preliminary results (outcomes and toxicity) of CIRT in the treatment of MPNSTs. PATIENTS AND METHODS: Our study retrospectively analyzed 13 patients (median age=54 years; range=23-72 years) with MPNST treated with CIRT for a median total dose of 73.6 Gy (relative biological effectiveness) (range=70.4-76.8 Gy) between 2013 and 2016. RESULTS: Six local progressions were recorded, with a median local progression-free survival of 23.2 months (range=2.2-45.4 months). Acute toxicities were mild. Late toxicity of grade 2 or more was noted in two patients. CONCLUSION: CIRT yielded good local control with a low rate of acute and late toxicities.

MRI evaluation of sacral chordoma treated with carbon ion radiotherapy alone.

BACKGROUND AND PURPOSE: To compare RECIST 1.1 with volume modifications in patients with sacral chordoma not suitable for surgery treated with carbon ions radiotherapy (CIRT) alone. To evaluate patients pain before and after CIRT. To detect if baseline Apparent Diffusion Coefficient values (ADC) from Diffusion Weighted sequences could predict response to treatment. MATERIAL AND METHODS: Patients included had one cycle of CIRT and underwent MRI before and after treatment. For each MRI, lesion maximum diameter and volume were obtained, and ADC values were analyzed within the whole lesion volume. Patients pain was evaluated with Numerical Rating Scale (NRS), considering the upper tumor level at baseline MRIs. RESULTS: 39 patients were studied (mean follow-up 18 months). Considering RECIST 1.1 there was not a significant reduction in tumor diameters (p = 0.19), instead there was a significant reduction in tumor volume (p < 0.001), with a significant reduction in pain (p = 0.021) if the tumors were above vertebrae S2-S3 at baseline MRIs. The assessment of baseline ADC maps demonstrated higher median values and more negative skewness values in progressive disease (PD) patients versus both partial response (PR) and stable disease (SD). CONCLUSIONS: Lesion volume measurement is more accurate than maximum diameter to better stratify the response of sacral chordoma treated with CIRT. Preliminary results suggest that baseline ADC values could be predictive of response to CIRT.

Spinal cord calcification in an early-onset progressive leukoencephalopathy.

Spinal cord calcifications are an unusual finding in pediatric neurology. We here describe a young child who presented severe psychomotor delay, tetraplegia, deafness, and anemia. Neuroradiological investigations revealed severe leukodystrophy and unusual calcifications in the cerebral white matter and all along the medullary pathways. Common infectious and metabolic diseases were ruled out. A mild reduction in the activity of several respiratory chain complexes was documented on muscle biopsy. Of interest, we found an intronic variant in DARS2, a gene involved in mitochondrial DNA translation, responsible for the syndrome of leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate. In our opinion, our case, and probably 2 previously reported Japanese siblings with a picture very similar to that of our patient, could represent a new, progressive leukoencephalomyelopathy.